Altered ripple density inside seizure onset zone in patients with focal cortical dysplasia‐associated epilepsy

Abstract Purpose To evaluate the clinical and stereoelectroencephalography (SEEG) features and postsurgical outcome in a uniform series of patients who underwent epilepsy surgery and had pathologically confirmation of focal cortical dysplasia (FCD). Methods We studied consecutive patients with drug‐refractory epilepsy who underwent SEEG recording. The high‐frequency oscillations (HFOs) features of SEEG, clinical characteristics, and surgical outcome were evaluated. Results Sixty patients (31 FCD type I, 13 II, and 16 III) were analyzed retrospectively. Patients with type II tended to have their seizures at an earlier age than those with I and III (p < .01). Six different ictal onset patterns (IOPs) were identified. In patients with temporal lobe epilepsy (TLE), the most common patterns were rhythmic spikes or spike waves and LFRS, and in patients with extratemporal epilepsy, the most common patterns were low‐voltage fast activity (LVFA) and rhythmic spikes or spike waves. In addition, ripple density was found to increase significantly from the interictal to ictal onset sections and from the ictal onset to ictal evolution sections in patients with FCD I (p < .001). Regarding the distinct IOPs, ripple density continued to increase significantly between the interictal and ictal onset sections in LVFA, rhythmic spikes or spike waves, and burst of high‐amplitude polyspikes (p < .05). Ripple density decreased between ictal onset and ictal evolution sections in patterns of LVFA and rhythmic spikes or spike waves (p < .05). The mean follow‐up duration was 2.7 years (range 1–4.2), and 66.7% (n = 40) were class I. Patients with subtypes III and II had favorable surgical outcome than those with I. Conclusion The clinical expression of seizure may depend on the pathological types with FCD II patients exhibiting their seizures at an earlier age. Distinct IOPs may demonstrate different ripple features and distinguishing the IOPs is very necessary to have an insight into the electrophysiological characteristics.


| INTRODUC TI ON
Focal cortical dysplasia (FCD) is one of the most common pathological substrates of refractory focal epilepsy. It was first described by Taylor et al. (1971) The exact cause of FCD is unclear, but cellular and/or architectural abnormalities such as irregular neurons and balloon cells during utero brain development or early postnatal injuries are closely related to FCD (Krsek et al., 2010). According to the International League Against Epilepsy (ILAE) classification, FCD is classified into three pathological subtypes. The Magnetic resonance imaging (MRI) changes and electro-clinical features of FCD subtypes are variable. High-MRI resolution has improved the identification, and localization of some forms of FCD types, electrocorticography (ECoG), or stereoelectroencephalography (SEEG) provides invasive windows for understanding the intrinsic epileptogenicity of FCDs.
More reports further suggested that high-frequency oscillations (HFOs) occurring on SEEG were biomarkers of the epileptogenic zone (Kerber et al., 2013;Ferrari-Marinho et al., 2015). In this study, we aimed to identify the electro-clinical features in a cohort of patients due to FCDs.

| Patients selection
Between January 2016 and December 2017, 109 patients underwent SEEG and resective surgery in our epilepsy center. We retrospectively analyzed 63 patients with surgical resection of the epileptogenic region and pathologically confirmation of focal cortical dysplasia (FCD).
A comprehensive evaluation including detailed historical data, neurological examination, long-term VEEG monitoring, and neuroimaging was performed among all the patients. In view of inconclusive or contradictive noninvasive evaluation, all the patients underwent SEEG with stereotactically placed intracranial electrodes to delineate the epileptogenic zone (EZ) precisely. The arrangement of multiple contacts electrodes (8-16 contacts with length 2 mm, diameter 0.8 mm, and 1.5mm apart) was designed individually according to the hypothesis of the EZ. The electrode position was confirmed by a postimplantation CT coregistered with the preimplantation MRI.

| SEEG recordings and analysis
The SEEG signals were recorded on a 128-channel Micromed EEG acquisition system (Micromed; Treviso, Italy) with a sampling rate of 512 or 1,024 Hz. During the monitoring of spontaneous seizures, the antiepileptic drug dosage was unchangeable. Intracerebral electrical stimulations were performed to map the eloquent cortex following the monitoring if necessary.
Five minutes of slow sleep segments during interictal periods were selected to detect high-frequency oscillations (HFOs), which remained about 80-250Hz. The automated detection of HFOs was performed according to the previous studies (Zijlmans et al., 2009).
The ictal onset zone and ictal onset patterns (IOPs) were identified visually based on the careful observation of all SEEG traces. The ictal onset sections (4-6s) and the seizure evolution (4-6s) sections were selected from the ictal SEEG for HFOs analysis (Perucca et al., 2014).
The IOPs-specific changes in HFOs density were investigated across the three SEEG sections.

| Postoperative follow-up
The surgical effect evaluations were performed 6 months postoperatively and then annually. Surgical outcome was classified according to Engel's classification: (Engel et al., 1993).

| Statistical analysis
Descriptive statistics were used for each variable among the three subtypes. The data were analyzed using one-way ANOVA, independent sample t test and chi-square test. Statistical analysis was performed using the SPSS 19.0 software package (IBM, Chicago, IL, USA). The significance level was set at 5% (p < .05).

| Ethical statement
The study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University, China, according to the Declaration of Helsinki. Written informed consent was obtained from all patients and their relatives.

| Clinical data
Three patients were lost to follow up. Sixty patients (26 men and 34 women) were analyzed retrospectively in this study. The mean age at epilepsy onset was 10.3 ± 6.0 years (range 0.4-28), mean age at surgery was 23.9 ± 9.3 years (range 5-52), and mean epilepsy duration was 13.6 ± 9.0 years (range 1-46). The localization of the EZ was frontal in 20 patients, temporal in 23 patients, parietal in 4 patients, occipital in 3 patients, and 6 patients had more than one lobe involvement (one parietal-occipital, 2 temporo-occipital, 2 temporoparietal, and one fronto-temporal), and 4 patients had insular involvement (one insular, 2 fronto-insular, and one fronto-temporo-insular).
Compared with FCD I and FCD III, FCD II patients tend to have their seizure at an earlier age (p = .008). The clinical data according to the FCD subtypes are summarized in Table 1, and Table 2 showed the detailed individual data.

| SEEG ictal onset patterns
Two patients did not have any seizure during the SEEG monitoring, and one patient had seizures originating with diffused slow waves, which had limited value to delineate the epileptogenic zone (EZ).
The three patients were excluded from further analysis. We finally identified six different IOPs. The most prevent pattern was rhythmic spikes or spike waves (25.0%), and then the second was low-voltage fast activity (LVFA) (23.3%), then the third was theta/alpha sharp activity (18.3%), the forth was burst of polyspikes (15.0%), and then the last two were slow-wave or baseline shift (10.0%) and LFRS (8.3%).
In patients with TLE, the most common patterns were rhythmic spikes or spike waves (27.3%) and LFRS (22.7%), and in patients with extratemporal epilepsy, the most common patterns were LVFA (28.9%) and rhythmic spikes or spike waves (23.7%). Four IOPs, rhythmic spikes or spike waves, theta/alpha sharp activity, slowwave or baseline shift, and LVFA were shared by each FCD subtypes.
LFRS were found only in FCD III, and burst of polyspikes was found in FCD I and II.

| Features of high frequency oscillations
Forty-three patients with sampling rate of 1,024 Hz were analyzed for ripples. Figures 1-3 showed the representative interictal SEEG patterns, ripple rate, and ripple density.
In patients with FCD I, ripple density inside SOZ was found to increase significantly from the interictal to ictal onset section, and decrease from the ictal onset to ictal evolution section (p < .001).
These findings did not apply to both FCD II and III subtypes. Figure 4 demonstrated the ripple rate of each of IOPs. In LVFA, rhythmic spikes or spike waves and burst of high-amplitude polyspikes, ripple density continued to increase significantly between the interictal and ictal onset sections (p < .05). In LVFA and rhythmic spikes or spike waves, ripple density decreased between the ictal onset and ictal evolution sections (p < .05). In slow-wave or baseline shift and theta/alpha sharp activity, ripples remained relatively stable after ictal onset. In LFRS, ripple density was found to decrease between ictal onset and ictal evolution, but the change did not reach statistical significance.

| Surgical, pathological outcomes and prognosis
The mean follow-up duration was 2.7 years (range 1-4.2). The post-

| D ISCUSS I ON
This study characterized the clinical and SEEG features in a cohort patients with histopathologically proven FCDs. Isolated FCDs were found in frontal, temporal, parietal, occipital, and insular lobes, but multilobar FCDs were located preferentially in parietal-occipital, temporo-occipital, and temporo-parietal. The frontal lobes were prone to present with FCD II, and the temporal lobes were prone to present with FCD I and II. Compared with subtypes I and III, type II patients have their first seizure at an earlier age. This confirmed that the occurrence and prevalence seem to be less dependent on the pathological types except the type 2b FCD (Najm et al., 2014). Less than 50% patients had MRI-visible lesions, and the positive rate was Age at onset, yrs (range) 10.3 ± 6.0 (0.4-28) 11.2 ± 5.3 (2-21) 5.9 ± 5.1 (0.4-17) 12.1 ± 6.5 (2-28)

TA B L E 1 Clinical characteristics according to the FCD subtypes
Age at surgery, yrs (range) 23.9 ± 9.3 (5-52) 24.5 ± 10.9 (5-52) 20.  lower in patients with FCD I than other subtypes. Surgical resection was the best treatment, and the surgical outcome depended on the histopathological subtypes. Patients with FCD subtype II and III had favorable outcome, and patients with FCD type I had the less favorable prognosis.
We found six distinct SEEG IOPs. Among these patterns, rhythmic spikes or spike waves and LVFA were the most common patterns. To assess the identified patterns across the different anatomical location of seizure onset, we classified the patients into temporal lobe group and extratemporal group. Patients with TLE were more presenting with rhythmic spikes or spike waves and that with FLE were more showing LVFA. Four IOPs, rhythmic spikes or spike waves, theta/alpha sharp activity, slow-wave or baseline shift, and LVFA were shared by each FCD subtypes.LFRS were found only in FCD III, and burst of polyspikes was found in FCD I and II.
HFOs, which consist of ripples and fast ripples, have been considered as an indicator of seizure onset zone (Crepon et al., 2010;Jacobs et al., 2009). Ripples appeared in the broader areas than fast ripples. It is challenging to identify that which ripple generator  The histogram demonstrating the ripple rate. The contacts (elA 7-9) showed the higher rate. (c) The raster showing the ripple density F I G U R E 4 Ripple rate of each of IOPs. In the patterns of LVFA, rhythmic spikes or spike wave and burst of highamplitude polyspikes, ripples inside the SOZ increased significantly between the interictal and ictal onset sections. In the patterns of LVFA and rhythmic spikes or spike waves, ripples inside the SOZ dropped between the ictal onset and ictal evolution sections. * compared with the interictal sections; ** compared with the ictal onset sections about the various FCD subtypes. In patients with FCD IIb, showing "tuber" or "tumor-like" high-FLAIR signal intensities, the area within the rich balloon cell density displayed the least epileptogenicity and the surrounding area within the less balloon cell density displayed the significant epileptogenicty (Boonyapisit et al., 2003).

ACK N OWLED G M ENTS
We appreciate the willingness of our patients to cooperate and for allowing their data to be used for this study. We are also grateful of the funding support. This work was supported by grants from the Beijing Natural Science Foundation (No. L182015), and Beijing Hospitals Authority' Ascent Plan (No. DFL20190801).

CO N FLI C T O F I NTE R E S T
None.

PEER R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1002/brb3.2169.